Selective and Bioavailable Inhibitors of Collagen Prolyl 4-Hydroxylase

Collagen is the most abundant protein in animals. A variety of diseases are associated with the overproduction of collagen including cancer metastasis. The stability of collagen relies on post-translational modifications that occur throughout the secretory pathway. One of the most important modifications is the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases (CP4Hs). Catalysis by CP4Hs converts proline residues to hydroxyproline residues, which are essential for the conformational stability of mature collagen strands. Importantly, CP4Hs are validated targets for the treatment of metastatic breast cancer, a significant unmet clinical need. Nonetheless, a therapy based upon this strategy has yet to emerge, primarily due to the difficulty in designing selective inhibitors for members of this enzyme family. Herein, we use a chemical approach based upon the classic 2,2′-bipyridine (bipy) scaffold to probe the active site of human CP4H1 and understand the determinants of selectivity for this...